Further improvement of circuit survival in citrate based continuous renal replacement therapy

ABSTRACT Background Continuous renal replacement therapy (CRRT) is the most frequently used modality of renal replacement therapy (RRT) in critical care patients with acute kidney injury (AKI). Adequate CRRT delivery can be challenging, due to problems with circuit patency. To improve circuit patency, we developed a new CRRT protocol using continuous veno-venous hemodiafiltration (CVVHDF) with 3.0 mmol/l regional citrate anticoagulation (CVVHDF/RCA3.0) as our first choice RRT modality. Methods Retrospective comparison of efficacy and safety of a CVVHDF/RCA3.0 protocol with our former continuous veno-venous hemofiltration protocol with 2.2 regional citrate anticoagulation (CVVH/RCA2.2) in adult critically ill patients with AKI requiring CRRT between 25 April 2020 and 24 October 2021. Results In total, 56 patients (257 circuits) and 66 patients (290 circuits) were included in the CVVH/RCA2.2 and CVVHDF/RCA3.0 groups, respectively. Median circuit survival was significantly higher in patients treated with CVVHDF/RCA3.0 (39.6 (IQR 19.5–67.3) hours) compared to patients treated with CVVH/RCA2.2 (22.9 (IQR 11.3–48.6) hours) (P < .001). Higher body weight and higher convective flow were associated with a lower circuit survival. Metabolic control was similar, except for metabolic alkalosis that occurred less frequently during CVVHDF/RCA3.0 (19% of patients) compared to CVVH/RCA2.2 (46% of patients) (P = .006). Conclusions CRRT circuit survival was longer with CVVHDF/RCA3.0 compared to CVVH/RCA2.2. CRRT circuit survival was negatively associated with higher body weight and higher convective flow.


INTRODUCTION
Continuous renal replacement therapy ( CRRT) is the most frequently used modality of renal replacement therapy ( RRT) in critical care patients with acute kidney injury ( AKI) [1 ].The debate regarding CRRT dose prescription in patients with AKI has been settled with guidelines advising a dose of 20-25 ml/kg/h [2 , 3 ].The actual delivery of this dose, however, can be challenging due to clotting in the CRRT circuit.Especially in patients with obesity and in patients with COVID-19 there is an increased risk for premature CRRT circuit failure [4 ].After circuit failure, the circuit needs to be replaced, which leads to temporal discontinuation ( downtime) of treatment.To increase the CRRT circuit patency and dose delivery, we developed a new CRRT protocol with continuous veno-venous hemodiafiltration ( CVVHDF) with 3.0 mmol/l regional citrate anticoagulation ( RCA) ( CVVHDF/RCA3.0) as our first choice RRT modality.
The aim of this study is to give a detailed analysis of the efficacy, safety, and practical implication of the CVVHDF/RCA3.0protocol compared to our former CRRT protocol with continuous veno-venous hemofiltration ( CVVH) with 2.2 mmol/l RCA ( CVVH/RCA2.2) .

Design
This retrospective observational cohort study was performed in the ICU of the University Medical Center Groningen ( UMCG) , The Netherlands and was conducted according to the principles of the Helsinki declaration.The local Medical Ethics Review Board reviewed and waived ( M22.289857) this study.

Population
All adult critically ill patients with ( acute) kidney injury requiring CRRT between 25 April 2020 and 24 October 2021.

CRRT treatment protocols
The decision to start CRRT was made by the treating ICU physician in consultation with the nephrologist.CRRT was performed using the Prismax ® ( Baxter, Brooklyn Park, MN, USA) with Prismaflex ST 150 ® filterset ( Baxter, Meyzieu Cedex, France) .Venous access was obtained with a double-lumen 13F central venous catheter ( high-flow double-lumen catheter; Baxter, Hechingen, Germany) .

Patients and allocation to treatment groups
All patients treated with CRRT between 25 April 2020 and 24 January 2021 ( period 1) were treated according the CVVH/RCA2.2protocol and are referred to as the "CVVH/RCA2.2group."All patients treated with CRRT between 25 January 2021 and 24 October 2021 ( period 2) were treated according to the CVVHDF/RCA3.0protocol and are referred to as the "CVVHDF/RCA3.0group."

Data collection
Patient and treatment data were routinely and prospectively stored in the UMCG standardized electronic health record system ( EPIC Systems, Verona, WI, USA) .Data were entered in REDCap ( Research Electronic Data Capture hosted at the UMCG) .Collected data included: [1 ]. patient characteristics [age, sex at birth, admission diagnosis, the Acute Physiology and Chronic Health Evaluation score 4 ( APACHE IV) score, presence of COVID-19 and chronic kidney disease ( CKD) , indication for CRRT, body length, and weight, type, and dose of anticoagulants], [2 ].Daily laboratory data recorded were: hematocrit, PT, aPTT, fibrinogen, total calcium, albumin, phosphate, and magnesium levels, and multiple times per day point of care blood-gas analyses including measurements of pH, pCO 2 , HCO      iii) circuits that were ended because of the decision to cease CRRT.Reasons for partial non-protocol treatment in period 1 were: heparin: ECLS ( extracorporeal life support system) treatment ( two patients) ; frequent clotting ( five patients) , no anticoagulation: therapeutic anticoagulation due to thrombosis ( one patient) ; liver failure ( one patient) , citrate, and heparin: COVID-19 ( six patients) , ECLS ( one patient) , other: modality switch from study period 1 to period 2 with exclusion of CRRT circuits of period 2 ( one patient) .Reasons for partly non-protocol treatment in period 2 were: heparin: ECLS ( five patients) ; liver failure ( two patients) , no anticoagulation: liver failure with bleeding tendency ( two patients) , citrate and heparin: ECLS ( two patients) ; COVID-19 ( three patients) .

Primary outcome
The primary outcome was CRRT circuit survival time in hours.
For this primary outcome analysis, we excluded circuits that were terminated because of [1 ] diagnostic procedures or interventions ( operations) outside the ICU [2 ], technical errors of the Prismax, and [3 ] circuits that were ended because of the decision to cease CRRT, since the survival time of these circuits does not reflect the performance of the CRRT protocols.

Sensitivity analyses
Since COVID-19 may influence the circuit survival time [4 , 6 , 7 ], we analyzed the circuit survival separately for patients with and without COVID-19.To facilitate a comparison with other studies, we also analyzed the median circuit survival time of the first circuit only.We also analyzed median survival time of all circuits, without exclusion of circuits that were terminated because of procedures outside the ICU, technical errors, or because of the decision to cease CRRT.The incidence of metabolic alkalosis was also analyzed according to a more sensitive definition: pH > 7.38 and HCO 3 − > 26 mmol/l [4 ] in patients who underwent a complete per protocol treatment.

Patient characteristics at CRRT start
Age, sex distribution, APACHE IV score, and the proportion of patients with COVID-19 and CKD were comparable for both groups ( Table 1 ) .

Effect of body weight and convective flow on CRRT circuit survival
Median CRRT circuit survival decreased with increasing body weight in both the CVVH/RCA2.2and CVVHDF/RCA3.0protocol group ( Fig. 3 ) .Within the protocolar body weight groups, as described in Appendix A ( Tables S1 and S2) , no correlation was found between body weight and circuit survival ( Figures S3,  Appendix B) .The hazard ratio of CRRT circuit failure also increased significantly with increasing convective flow in an overall analysis including both groups ( hazard ratio per increase of 100 ml convective flow: 1.05 ( 95% CI: 1.02-1.09); P < .001)( Fig. 4 ) .

Sensitivity analyses
The median circuit survival in patients without COVID-19 was significantly longer in the CVVHDF/RCA3.0 group compared with the CVVH/RCA2.) .An increased total calcium/iCa ratio according to a more sensitive definition ( > 2.25) , as applied in our institution, at any time during CRRT treatment occurred in 12.8% and 11.5% of patients in the CVVH/RCA2.2and CVVHDF/RCA3.0groups, respectively ( P = .85) .

Patient and renal outcomes
Patient and renal outcomes did not significantly differ between both groups ( Table 7 ) .

DISCUSSION
The main findings of this study are that circuit survival time was significantly longer in patients treated with the CVVHDF/RCA3.0protocol compared with those treated with the CVVH/RCA2.2protocol.In addition, both a higher body weight and higher convective flow were associated with lower circuit survival time.
Notably, the CVVHDF/RCA3.0protocol differs in three aspects from the CVVH/RCA2.2protocol: [1 ] the convective flow was lowered albeit with a near-identical total clearance [2 ], the citrate dose was increased, and [3 ] also in non-COVID-19 patients CRRT circuits were primed with 10.000 IU heparin.Therefore, we cannot determine which of the three factors is responsible for the increase in circuit survival.Possibly the lower convective flow  Calcium-magnesium-chloride solution a replacement rate ( ml/min) ( median ( IQR) ) 0.11 ( 0.09-0.12)0.17 ( 0.15-0.17   in the CVVHDF/RCA3.0 group is the dominant factor explaining the increase in circuit survival time.This suggestion is based on the negative association between the convective flow and CRRT circuit survival time, which is probably a consequence of the lower filtration fraction with CVVHDF treatment.Additionally, higher body weight ( that determines the individual convective flow) resulted in decreased CRRT circuit survival.Although, we cannot prove that the convective flow is responsible for the relationship between body weight and circuit survival, this is plausible, since within protocolar body weight groups ( having the same convective flow and a different weight within the specific weight group) there was no association between body weight and circuit survival [Appendix A ( Tables S1 and S2) ].CRRT circuit survival with CVVHDF was also significantly higher compared to CVVH in a small Chinese randomized controlled trial [8 ] and in a post hoc multivariate analyses in the RICH trial [9 ].In another small randomized crossover study, circuit survival was also significantly longer during CVVHDF compared with CVVH, but the prescribed CRRT dose was lower in the CVVHDF group [10 ].Concerning citrate dose, in a 2006 study CRRT circuit survival was compared between two patient groups with the same CRRT protocol except for a difference in the citrate concentration in the prefilter substitution fluid ( 23 mmol/l versus 18 mmol/l) .In this study, a higher citrate dose did not increase CRRT circuit survival time, but did result in a higher incidence of metabolic alkalosis defined as pH ≥ 7.50 ( 75% compared to 28% of patients; P = .001)[11 ].In another CRRT study comparing RCA doses of 2.5 and 3.0 mmol/l also no differences in CRRT circuit survival were found [12 ].However, adjustments in citrate doses based on post-filter iCa levels resulted in too little contrast in the citrate dose between the groups.Incidences of citrate accumulation were low in both treatment groups.The use of Biphozyl ( HCO 3 − 22 mmol/l) instead of Phoxilium ( HCO 3 − 30 mmol/l) in the CVVHDF/RCA3.0 group allowed us to use a higher citrate dose with even lower incidences of metabolic alkalosis ( 19% in the CVVHDF/RCA3.0 group and 46% in the CVVH/RCA2.2group; P = .006) .Apart from the development of metabolic alkalosis, metabolic control was similar in both protocol groups.Future studies should investigate whether CRRT circuit survival can indeed be improved by selectively lowering of convective flow with an equivalent increase in dialysate flow to maintain the same total CRRT dose.These future studies should investigate whether in obese patients a lower delivered dose per kg body weight does optimize CRRT circuit patency.A lower dose per kg body weight might be justified, since total body water in obese patients does not increase relative to the increase in body weight.There is currently no evidence-based method to adjust for this effect.In the meantime, the adjustment that was used in the ATN-trial ( adjusted body weight = ideal body weight plus 25% of the difference between ideal and actual weight at ICU admission) can likely be applied [13 ].
The comparison of the CRRT circuit survival between this and other studies is hampered due to differences in patient selection and a large variation in criteria for selection and replacement of CRRT filters.This heterogenicity becomes evident in the individual studies included in a recent meta-analyses on CRRT survival [14 ], where three studies included all circuits during treatment [9 , 15 , 16 ], while other studies included either only the first circuit [17 -21 , 22 ], the first two [23 ] or four circuits [24 ], and CRRT circuits were not routinely replaced after 72 hours in three out of 12 studies [16 , 22 , 23 ].Not replacing CRRT filters after 72 hours will lead to higher CRRT circuit survival times.Including only the first, or up to four circuits will also cause overestimation of CRRT survival times.Circuit survival of the first circuit in our study was also higher ( Table S6, Appendix B) compared to circuit survival in the primary outcome analysis ( Table 4 ) .
Body weight was not mentioned in five studies [16 , 17 , 19 , 23 , 24 ] included in the recent meta-analysis [14 ], while we found that body weight might be an important determinant of CRRT circuit survival.We decided to include all patients on RCA based CRRT while others excluded patients with a CRRT duration < 3 days [19 ], patients with CKD with prior dependency on dialysis [9 , 18 , 20 ], or patients who received a kidney transplant < 12 months ago [9 ].
The strength of our study is the high number of included CRRT circuits in both protocol groups with detailed treatment and laboratory data.Our study has also several limitations due to its retrospective character, due to which some patients received a complete per protocol treatment and others only partial.This, however, reflects clinical practice with a considerable number of patients with liver failure, on extracorporeal life support or with COVID-19 during the study period.We cannot exclude a training effect in study period 2 due to the introduction of the new protocol.We did not routinely measure post-filter iCa levels in the extracorporeal circuit.There is also debate as to whether postfilter iCa levels can be used to assess treatment performance, because analyzers might not reliable assess iCa levels outside the physiological range [25 ].Since we included all CRRT circuits with clear exceptions we are confident that our findings do represent the actual performance of both protocols in our tertiary academic mixed ICU patient population.

Figure 1 :
Figure 1: Flowcharts of patients and circuit selection in both protocol groups.1 = circuit termination because of ( i) diagnostic procedures or interventions outside the ICU, ( ii) technical errors of the Prismax, and ( iii) circuits that were ended because of the decision to cease CRRT.Reasons for partial non-protocol treatment in period 1 were: heparin: ECLS ( extracorporeal life support system) treatment ( two patients) ; frequent clotting ( five patients) , no anticoagulation: therapeutic anticoagulation due to thrombosis ( one patient) ; liver failure ( one patient) , citrate, and heparin: COVID-19 ( six patients) , ECLS ( one patient) , other: modality switch from study period 1 to period 2 with exclusion of CRRT circuits of period 2 ( one patient) .Reasons for partly non-protocol treatment in period 2 were: heparin: ECLS ( five patients) ; liver failure ( two patients) , no anticoagulation: liver failure with bleeding tendency ( two patients) , citrate and heparin: ECLS ( two patients) ; COVID-19 ( three patients) .

Figure 3 :
Figure 3: Circuit survival: effect of body weight.Median circuit survival ( with interquartile range) per protocolar weight group.Median CRRT circuit survival declined with increasing body weight.Overall circuit survival ( both protocol groups together) was significantly lower in body weight categories above 100 kg compared to the body weight category 71-86 kg.Median CRRT circuit survival was significantly higher in the CVVHDF/RCA3.0protocol group compared to the CVVH/RCA2.2protocol group in body weight categories 71-86 kg ( P = 0.00003) , 100-114 kg ( P = 0.03) , and > 115 kg ( P = .004) .

Figure 4 :
Figure 4: Effect of convective flow on circuit survival.Graphical representation of the association between convective flow and the risk of CRRT circuit failure taking the CRRT circuits from both protocol groups together ( n = 347) , after exclusion of CRRT circuits ended because of machine errors, procedures outside the ICU or the decision to cease CRRT.The blue line shows the hazard ratio for circuit failure.The shaded area correspondents to the 95% pointwise confidence interval.

Figure 5 :
Figure 5: Pattern of electrolytes and acid/base balance during the first 5 days of full course per protocol treatment.Figures are based on data of patients with a complete per protocol treatment in CVVH/RCA2.2( 39 patients, blue line) and in CVVHDF/RCA3.0( 52 patients, orange line) .Left panel: the first 21 hours after start of CRRT.Right panel: the first 5 days after start of CRRT.

Figure 6 :
Figure 6: Courses of parameters of citrate metabolism.Figures are based on data of patients with a full course per protocol treatment ( 39 patients CVVH/RCA2.2;52 patients CVVHDF/RCA3.0) .Left panel: the first 21 hours after start of CRRT, Middle panel: the first 5 days after start of CRRT, Right panel: the first 5 days after start of CRRT. 1 1

and circuit selection for primary outcome analyses Patient and circuit selection for primary outcome analyses Selection for primary endpoint analyses (CRRT circuit survival
• 25 patients • 122 circuits Patient ) • 50 patients • 179 circuits Selection for primary endpoint analyses (CRRT circuit survival) • 41 patients • 168 circuits

Table 1 : Baseline characteristics at ICU admission.
Data were analyzed with R version 4.2.2 ( Vienna, Austria) ( http:// cran.r-project.org/) .Baseline data ar e expr essed as means ( ± SD) 95% or medians ( interquartile ranges) .Comparisons between the groups were made using Student's t -test, chi square ( two sided) , or Mann-Whitney U -test, as appropriate.P < .05 was considered statistically significant.CRRT circuit survival was analyzed using frailty Cox proportional hazard models, adjusted for sex, body weight, age, COVID-19, and APACHE IV score.

Table 2 : Laboratory parameters prior to the start of CRRT.
Data to calculate the anion gap were missing in two patients in the CVVH/RCA2.2group. a